NanO2 as a Cerebroprotectant in a tMCAO Stroke Model in Mice

NanO2 作为小鼠 tMCAO 中风模型中的脑保护剂

• 批准号: 10324026
• 负责人: Helena Willington Morrison
• 金额: $ 47.81万
• 依托单位: NUVOX PHARMA, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10324026
• 关键词: Acute; Address; Adult; Affect; Age; Alteplase; American; Anesthesia procedures; Animals; Applications Grants; Behavior; Blinded; Blood flow; Caring; Clinic; Clinical; Clinical Trials; Coagulation Process; Confounding Factors (Epidemiology); Data; Development; Diabetic mouse; Dose; Educational workshop; Emulsions; Ensure; Female; Filament; Future; Grant; Hospitals; Hour; Infarction; Injury; Insulin-Dependent Diabetes Mellitus; Ischemia; Ischemic Stroke; Laboratories; Magnetic Resonance Imaging; Measurement; Measures; Mechanics; Medical; Middle Cerebral Artery Occlusion; Modeling; Mus; National Institute of Neurological Disorders and Stroke; Neurons; Neuroprotective Agents; Operative Surgical Procedures; Oryctolagus cuniculus; Outcome; Oxygen; Patient Transfer; Patients; Pharmaceutical Preparations; Phase; Phase Ib/II Trial; Placebos; Play; Procedures; Randomized; Rattus; Regimen; Reperfusion Therapy; Reproducibility; Research; Risk; Role; Route; Severities; Small Business Technology Transfer Research; Stroke; Survival Analysis; Techniques; Testing; Therapeutic; Thrombectomy; Time; Tissue Preservation; Tissue Viability; United States National Institutes of Health; Weight; aged; anaerobic glycolysis; clinical candidate; cohort; comorbidity; cost; experience; functional outcomes; male; mortality; mouse model; normotensive; novel; perfluoropentane; phase II trial; pre-clinical; pre-clinical assessment; preclinical study; programs; sex; standard of care; stroke model; stroke outcome; stroke patient; stroke therapy; tissue oxygenation

PROJECT SUMMARY/ABSTRACT Stroke affects more than 795,000 patients per year in the US, kills approximately 140,000 and is the single largest cause of expense for long-term medical care in the US. About 87% of strokes are ischemic, 40% of which are large vessel occlusions (LVO). Acute ischemic stroke (AIS) can be treated by restoring blood flow, e.g. by using the clot- busting drug t-PA for eligible patients. Recently, mechanical thrombectomy (MT) has emerged as standard of care for LVO stroke. As MT is a specialized procedure, up to 60% of thrombectomy patients are first evaluated at spoke hospitals and then transferred to a hub hospital for MT. The duration of time for patient transfer from the spoke to the hub is variable and may be in excess of several hours. Reperfusion with tPA also takes time, usually several hours for adequate blood flow to be obtained. A safe drug which maintained oxygenation within the at-risk region in AIS could preserve the tissue until reperfusion is attained, thereby increasing the utility of reperfusion therapy. NuvOx Pharma is developing a novel oxygen therapeutic, NanO2TM (2% w/vol dodecafluoropentane emulsion). In multiple animal studies in stroke, NanO2 maintained the tissue viability in the penumbra and reduced the volume of infarct by 85%. In a Phase Ib/II trial in AIS patients, NanO2 was safe at all dose levels (0.05, 0.10 & 0.17 mL/kg) administered 3 times 90 minutes apart and was shown to be efficacious. The high dose cohort had a significant improvement compared to placebo in the functional end-point of the modified Rankin scale at 30 and 90 days (P = 0.01 and P=0.03, respectively). NuvOx has an active IND for a Phase II trial called the PROVEN trial (Phase II to Restore Oxygen in LVO patients En Route for MT using NanO2). We hypothesize that early administration of NanO2 to AIS patients will maintain viability of tissue in the penumbra until reperfusion can be attained. The NINDS has developed the Stroke Preclinical Assessment Network (SPAN) program to find neuroprotective agents to bring to the clinic. To make the NanO2 program competitive with these neuroprotectants in an application to NIH StrokeNet in the future, NuvOx must ensure the scientific rigor and reproducibility of our preclinical studies match the standard of SPAN. Our preclinical data is promising, but lacks the inclusion of aged animals, other comorbidities for stroke and long-term functional outcome measurements. In this Phase I STTR grant application, we propose to conduct studies of NanO2 in a transient middle cerebral artery occlusion (tMCAO) mouse model using the intraluminal filament technique. The study will be conducted in two phases, first in healthy mice to establish the model with less confounding variables followed by a second phase in aged mice and mice with comorbidities. Successful completion of the Aims of this study will fulfill the NIH’s requirement for rigor and reproducibility so that NanO2 can be considered as a candidate for clinical trials in StrokeNet and other organizations supported by NIH.

项目概要/摘要 在美国，中风每年影响超过 795,000 名患者，导致约 140,000 人死亡，是最大的单一疾病 在美国，大约 87% 的中风是缺血性中风，其中 40% 是大面积中风。 血管闭塞（LVO）可以通过恢复血流来治疗，例如使用凝血剂。 最近，机械血栓切除术 (MT) 已成为护理标准。 由于 MT 是一项专门的手术，因此高达 60% 的血栓切除术患者首先在轮辐处进行评估。 医院然后转移到中心医院进行 MT 患者从分支医院转移到中心医院的持续时间。 中枢是可变的，可能会超过几个小时。tPA 的再灌注也需要时间，通常是几个小时。 获得足够血流的安全药物，可维持危险区域内的氧合。 AIS 中的 AIS 可以保留组织直至达到再灌注，从而增加再灌注治疗的效用。 NuvOx Pharma 正在开发一种新型氧治疗剂 NanO2TM（2% w/vol 十二氟戊烷乳液）。 多项针对中风的动物研究表明，NanO2 维持了半暗带中的组织活力并减少了体积 在 AIS 患者的 Ib/II 期试验中，NanO2 在所有剂量水平（0.05、0.10 和 0.17 mL/kg）下都是安全的。 给药 3 次，间隔 90 分钟，结果表明高剂量组有显着效果。 与安慰剂相比，30 天和 90 天时改良 Rankin 量表的功能终点有所改善（P = 分别为 0.01 和 P=0.03，NuvOx 拥有一项名为 PROVEN 试验的 II 期试验的活跃 IND（II 期至 使用 NanO2 恢复 LVO 患者在 MT 途中的氧气 我们捕捉到了 NanO2 的早期给药。 AIS 患者将维持半影组织的活力，直到实现再灌注。 NINDS 开发了中风临床前评估网络 (SPAN) 计划来寻找神经保护药物 使 NanO2 项目在应用中与这些神经保护剂竞争。 未来，对于 NIH StrokeNet，NuvOx 必须确保我们临床前研究的科学严谨性和可重复性 符合 SPAN 的标准，我们的临床前数据很有希望，但缺乏老年动物和其他动物的纳入。 中风合并症和长期功能结果测量 在第一阶段 STTR 拨款中。 应用，我们建议进行 NanO2 在短暂大脑中动脉闭塞中的研究 (tMCAO) 使用腔内灯丝技术的小鼠模型该研究将分两个阶段进行。 首先在健康小鼠中建立混杂变量较少的模型，然后在老年小鼠中进行第二阶段 成功完成本研究的目标将满足 NIH 的要求。 的严谨性和可重复性，因此 NanO2 可以被考虑作为 StrokeNet 和 NIH 支持的其他组织。